Rs1800562

This SNP has been recognized by the Coriell Personalized Medicine Collaborative ICOB. Additional information is available here

rs1800562 represents a SNP that accounts for ~85% of all cases of hemochromatosis, a disorder whose symptoms include cirrhosis of the liver, diabetes, hypermelanotic pigmentation of the skin, and heart failure. OMIM indicates that liver cancer is responsible for about one-third of deaths of rs1800562(A;A) homozygotes, and since hemochromatosis is a relatively easily treated disorder if diagnosed, this is a form of preventable cancer.

The rs1800562(A) allele is known as the C282Y mutation, and it is found at a frequency of around 5-10% in many Caucasian populations, leading to an incidence of (A;A) homozygotes around 1 in 200. Early identification of rs1800562(A;A) homozygotes can prevent complications of hemochromatosis; however, the percentage of all (A;A) homozygotes who actually develop clinical signs of hemochromatosis may be relatively low, may depend on sex (see below), and appears to be influenced by other SNPs yet to all be discovered as well as (unidentified) environmental factors, possibly including the amount of iron in the diet.

In rs1800562(A;A) patients who do develop hemochromatosis, a SNP has been identified which increases the risk of cardiomyopathy (a form of heart disease). rs4880(T;T) homozygotes are at ~10 fold increased risk for dilated- or non-dilated cardiopathy based on a study of 217 patients.[PMID 15591282]

rs235756, a SNP in the BMP2 gene, is another SNP that may influence the development of hemochromatosis in rs1800562(A;A) individuals, at least if serum transferrin levels are a good indication. Transferrin levels increased with increasing copies of the rs235756(T) allele.[PMID 17847004]

So which rs1800562(A;A) individuals actually develop clinical signs of hemochromatosis? In a recent study of ~200 rs1800562(A;A) homozygotes, ~30% of the males had iron-overload related diseases versus 1% of the females. Male C282Y homozygotes with a serum ferritin level of 1,000 mcg per liter or more were more likely to report fatigue, use of arthritis medicine, and a history of liver disease than were men who lacked a rs1800562(A) allele.[PMID 18199861]

Women who are rs1800562(A) homozygotes are less affected by hemochromatosis due to elimination of excess iron during menstruation, but may become affected after menopause.

Carriers of rs1800562(A) may be affected by a mild form of hemochromatosis if also a carrier of rs1799945(G) H63D.

According to Coriell, in Caucasian populations:

• (A;A) - 0.4% of individuals, carrying 2 copies of the risk variant (33-57% of such males will have quite elevated iron levels; 3-16% if female)
• (G;A) - 12% carry 1 copy of the risk variant and 1 copy of the non-risk variant
• (G;G) - 87.6% carry (only) the non-risk variant

GWAS snp
PMID	[PMID 19084217]
Trait	Serum markers of iron status
Title	Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels
Risk Allele
P-val	4E-15
Odds Ratio	NR NR

GWAS snp
PMID	[PMID 19820697]
Trait	Hematological parameters
Title	A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium
Risk Allele	A
P-val	1E-23
Odds Ratio	1.41 [1.13-1.69] fl increase

GWAS snp
PMID	[PMID 19820699]
Trait	Serum markers of iron status
Title	Common variants in TMPRSS6 are associated with iron status and erythrocyte volume
Risk Allele	A
P-val	5E-7
Odds Ratio	0.20 [0.12-0.28] SD increase

GWAS snp
PMID	[PMID 19862010]
Trait	Hematocrit
Title	Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium
Risk Allele	A
P-val	2E-9
Odds Ratio	0.31 [0.21-0.41] % increase

[PMID 20029940] Suggestive synergy between genetic variants in TF and HFE as risk factors for Alzheimer's disease

[PMID 20858683] Common variants at ten genomic loci influence hemoglobin A1C levels via glycemic and non-glycemic pathways

GWAS snp
PMID	[PMID 20927387]
Trait
Title	A genome-wide association study of red blood cell traits using the electronic medical record
Risk Allele	A
P-val	3E-9
Odds Ratio	0.49 [0.33-0.65] unit increase

GWAS snp
PMID	[PMID 21665994]
Trait
Title	Genome-wide association study identifies two loci strongly affecting transferrin glycosylation.
Risk Allele	A
P-val	2E-32
Odds Ratio	0.6290 [0.53-0.73] unit decrease

GWAS snp
PMID	[PMID 21785125]
Trait
Title	Association of HFE and TMPRSS6 genetic variants with iron and erythrocyte parameters is only in part dependent on serum hepcidin concentrations.
Risk Allele
P-val	3E-7
Odds Ratio	0.3890 [0.24-0.54] ng/ml increase

GWAS snp
PMID	[PMID 21943158]
Trait
Title	Genetic variants in LPL, OASL and TOMM40/APOE-C1-C2-C4 genes are associated with multiple cardiovascular-related traits.
Risk Allele	A
P-val	5E-12
Odds Ratio	0.1770 [0.13-0.23] mg/l increase

GWAS snp
PMID	[PMID 20686565]
Trait
Title	Biological, clinical and population relevance of 95 loci for blood lipids.
Risk Allele	A
P-val	6E-10
Odds Ratio	2.2200 None